Multistage carcinogenesis has been demonstrated for the rat urinary bladder using N-(4-(5-nitro-2-furyl)-2-thiazolyl) formamide (FANFT) as initiator and sodium saccharin as promoter. However, feeding of sodium saccharin to rats with a rapidly proliferating bladder mucosa also resulted in bladder tumors, even without FANFT initiation. Since sodium saccharin is not a mutagenic, is not metabolically activated to a reactive electrophile, and does not bind to DNA, these results suggest that carcinogenesis occured without a mutation. The tissue kinetics of the early phases of the process will be evaluated by scanning electron microscopy and autoradiography, and the reversibility and time of application of the sodium saccharin will be examined. The possibility of contamination of the urine by bacteria, nitroso compound or other potential mutagens will also be evaluated. Although a mutation appeared not to be involved, other genetic changes involving chromosomal rearrangements could play a role. Karyotype analyses will be performed of papillomas and carcinomas to begin evaluating this possibility. Evaluation of the interaction of sodium saccharin with cellular components will also be attempted.